This application is for renewal of a grant that has supported a long-term investigation of mechanisms of nociception and antinociception. The objective of the proposed studies is to learn about how plastic changes in nociceptive responses lead to persistent pain and to discover new approaches to therapeutic targets for treatment of chronic pain. The hypotheses of this proposal are: 1) calcitonin gene-related peptide and substance P are neuropeptide transmitters that help trigger central sensitization in an animal model of acute inflammation, intradermal injection of capsaicin; they do this by activating a number of signal transduction cascades in nociceptive dorsal horn neurons; 2) activation of the PI3K and Akt/PKB signal transduction cascade is important for the development of peripheral and central sensitization following intradermal injection of capsaicin; and 3) the mechanical allodynia and hyperalgesia produced by administration of Nerve Growth Factor and of Brain-derived Neurotrophic Factor is mediated in part by activation of the Akt/PKB signaling pathway. The experiments will include Western blots, immunohistochemistry, behavioral studies, and electrophysiological recordings from nociceptive dorsal horn neurons. Preliminary evidence supports the feasibility of the work and suggests that the results could lead to a number of new targets for improvements in pain therapy.